Polymer complexes of glucuronoglucanes

ABSTRACT

A biocompatible intermolecular polymer complex comprises an anionic component and a non protein cationic component. The anionic component comprises a linear or branched polysaccharide chain wherein at least 5% of the basic structural units are glucuronic acid. The cationic component comprises a linear or branched natural, semi-synthetic or synthetic oligomer or polymer.

INTRODUCTION

[0001] Oxidised cellulose and its derivatives have been widely used inmedicine and pharmacy since the first preparation by Chait and Kenyon[Shorygin P P., Chait E. V.: Zh. obshch. chim. 7,188 (1937); Yackel E.C., Kenyon W. O.: J. Am. Chem. Soc. 64, 121 (1942)].

[0002] Other types of haemostatics and antifibrinolytics have beenintroduced, however, oxidised cellulose especially in the highly pureform of a polyanhydroglucuronic acid and their copolymers (PAGA), andnotably salts thereof, is used in various medicinal applications as acompletely resorbable semi-synthetic polymer with minimum adverseeffects in the organism. This is true for both the basic substanceprepared according to GB 709684; U.S. Pat. No. 4,100,341, or saltsthereof prepared according to more recent patents, such as.: CS AO242920; EP 0659440A1 and PCT IE 98/00004.

[0003] It is known that after application of oxidised cellulose to stopsurface bleeding a rigid scab is formed, especially on movable parts ofthe body, such as knees, fingers or ankles. This may be a disadvantagebecause it can crack and lead to renewed bleeding. Using a haemostataccording to PCT IE 98/00004 this disadvantage can be partially overcomeby altering the technological conditions of the manufacture (such asincreasing the amount of crosslinks) which brings about increasedaccumulation of the body fluids in the substance and thereby theflexibility of the wound cover is optimised.

[0004] Within the last two decades, during investigations of varioustypes of polysaccharides, it was established that during theirbiodegradation in the living organism, certain functions of varioustypes of cells are influenced. [Berger J., Nemec J., Sedlmayer P.,Vortel V.: Report on Toxicological Investigation of a New DrugPreparation “Mikrocel”, Internal report, Research Institute for Pharmacyand Biochemistry, Praha, branch Pardubice-Rosice and Labem, 1984;Burchard W.: Polysacharide, Eigenschaften und Nutzung, Springer-Verlag,Berlin, Heidelberg, N.Y., Tokyo, p. 144 (1985); U.S. Pat. No.5,166,137]. Depending on the type of bond in the main glycosydic chain,on the value of the degree of polymerisation, on the presence of variousfunctional groups, and the degree of ionisation thereof, on the type ofstructural units, and the type of salt or a complex salt thereof, thesepolysaccharides affect the immune system of the organism. It seems forinstance that glucanes bonded by an 1,3 β bond have immunomodulativeproperties while 1,4 β bonded glucanes suppress tumorous growth. Thereare however exceptions to these rules. An important factor underlyingthese properties is the presence of the glucuronic acid in the chain.

[0005] It is known that a large proportion of bonds between individualsubstances occurring in living organisms is of a non-covalent nature,such as hydrogen bonds, van der Waals forces, or bonds of an ioniccharacter especially with biopolymers. These bonds create so-calledintermolecular polymeric complexes (IMC) such as for example,heparin-peptides. In general these complexes represent a new class ofmacromolecular substances formed by association of individual polymerchains into macromolecules through secondary bonding interactions.According to the nature of the interactions these complexes can besubdivided into polyelectrolyte complexes, hydrogen bonded complexes,stereo complexes and charge transfer complexes. These types of complexeshave a number of common properties, notably an organised supermolecularstructure and the ability to create other higher supermolecularentities. The characteristic feature is their ability to undergorestructuring depending on the conditions prevailing in theirenvironment. Further they are capable of undergoing interpolymersubstitution reactions and it is especially due to this latter abilitythat the IMCs in their behaviour come close to imitating biochemicalprocesses occurring in living organisms.

[0006] The invention in particular involves the use ofpolyanhydroglucuronic acids and salts thereof. The termpolyanhydroglucuronic acid and salts there of as used herein alsoincludes copolymers thereof, especially with anhydroglucose. This ishereinafter referred to as PAGA.

[0007] Co-pending patent application PCT IE98/00004 describes particularpolyanhydroglucuronic acids and salts thereof and a method of preparingsuch compounds. In particular therefore, the term polyanhydroglucuronicacids and salts thereof includes the acids and salts referred to in thisco-pending application.

STATEMENTS OF INVENTION

[0008] According to the invention there is provided a biocompatibleintermolecular polymer complex of:

[0009] an anionic component comprising a linear or branchedpolysaccharide chain wherein at least 5%. of the basic structural unitsare glucuronic acid; and

[0010] a non protein cationic component comprising a linear or branchednatural, semi-synthetic or synthetic oligomer or polymer.

[0011] In a preferred embodiment of the invention the cationic componentcontains nitrogen that either carries a positive charge or wherein thepositive charge is induced by contact with the polysaccharidic anioniccomponent.

[0012] In one case the cationic component is selected from derivativesof acrylamide, methacrylamide and copolymers thereof. Preferably thecationic component is selected from polyacrylamide, copolymer ofhydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers ofacrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate.

[0013] In another case the cationic component is a cationised naturalpolysaccharide. Preferably the polysaccharide is a starch, cellulose orgum. The gum may be guargumhydroxypropyltriammonium chloride.

[0014] In another case the cationic component is a synthetic orsemi-synthetic polyamino acid. Preferably the cationic component ispolylysin, polyarginin, or α,β-poly-[N-(2-hydroxyethyl)-DL-aspartamide].

[0015] In a further embodiment the cationic component is a syntheticanti-fibrinolytic. The anti-fibrinolytic may be a hexadimethrindibromide(polybren).

[0016] In a still further embodiment the cationic component is a naturalor semi-synthetic peptide. Preferably the peptide is a protamine,gelatine, fibrinopeptide, or derivatives thereof.

[0017] In a further case the cationic component is an aminoglucane orderivatives thereof. Preferably the aminoglucane is fractionated chitinor its de-acetylated derivative chitosan. The aminoglucane may be ofmicrobial origin or is isolated from the shells of arthropods such ascrabs.

[0018] In a preferred embodiment of the invention the anionic componentis polyanhydroglucuronic acid and/or bicompatible salts thereof.

[0019] In this case preferably the polyanhydroglucuronic acid and saltsthereof contain in their polymeric chain from 8 to 30 percent by weightof carboxyl groups, at least 80 percent by weight of these groups beingof the uronic type, at most 5 percent by weight of carbonyl groups, andat most 0.5 percent by weight of bound nitrogen. Preferably thepolyanhydroglucuronic acid and salts thereof contain in their polymericchain at most 0.2 percent by weight of bound nitrogen.

[0020] In a preferred embodiment the molecular mass of the polymericchain of the anionic component is from 1×10³ to 3×10⁵ Daltons, ideally,the molecular mass of the polymeric chain of the anionic componentranges from 5×10³ to 1.5×10⁵ Daltons.

[0021] Most preferably the content of carboxyl groups is in the range offrom 12 to 26 percent by weight, at least 95 percent of these groupsbeing of the uronic type.

[0022] In a preferred embodiment of the invention the anionic componentcontains at most 1 percent by weight of carbonyl groups.

[0023] The carbonyl groups are preferably intra- and intermolecular 2,6and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.

[0024] The cationic component may be gelatine.

[0025] Alternatively the cationic component is chitosan.

[0026] The invention also provides a pharmaceutical or cosmeticcomposition including at least one biocompatible complex of theinvention.

[0027] Preferably the composition includes at least one biocompatiblebiologically active substance.

[0028] The composition may alternatively or additionally include atleast one biologically acceptable adjuvant.

DETAILED DESCRIPTION

[0029] We have now found that by preparing polymeric intermolecularcomplexes (IMC) of glucuronoglucanes, notably microdispersed PAGA,prepared especially according to PCT IE 98/00004 it is possible toenhance the haemostatic effect of the final products on this basis andthe properties of the temporary wound cover formed after the haemostasisis achieved such as its flexibility and resistance to cracking onmovable parts of the body.

[0030] It is also possible to upgrade physicomechanical properties ofthe final products on this basis. Such IMCs make it possible to prepareapplication forms whose manufacture from a pure PAGA or their simplesalts is extremely difficult. Such application forms includes non-woventextile-like structures or polymeric films. To modify or upgrade thephysical mechanical properties it is sufficient to use even a relativelysmall amount of polymeric counterion while it is possible to obtainsuitable application properties within a broad concentration range ofthe components. The ratio of the glucuronoglucane to polymericcounterion can be 0.99:0.01 to 0.01:0.99.

[0031] Another advantage of glucuronoglucane based IMCs is thepossibility to control their biological properties such as varying thedegree of haemostatis, resorption time, or immunomodulative properties,and the like.

[0032] Polymeric cations suitable to form IMCs with glucuronoglucanesprepared for example according to PCT IE 98/00004 may roughly besubdivided into the following groups:

[0033] 1. Synthetic biocompatible nitrogen-containing oligomers andpolymers.

[0034] a) Derivatives of acrylamide and methacrylamide and theircopolymers [such as polyacrylamide, copolymer of hydroxyethylmetacrylateand hydroxypropylmetacrylamide, copolymer of acrylamide, butylacrylate,maleinanhydride, and methylmetacrylate, and the like], or elsecationised natural polysaccharides such as starches, celluloses, or gumssuch as guargumhydroxypropyltriammonium chloride.

[0035] b) Synthetic or semi-synthetic polyaminoacids such as polylysin,polyarginin, α,β-poly-[N-(2-hydroxyethyl)-DL-aspararide. Syntheticantifibrinolytics hexadimethrindibromide (polybren) can also be includedin this group.

[0036] 2. Natural or semi-synthetic peptides such as gelatine,protamines, or fibrinopeptides, and their derivatives.

[0037] 3. Natural aminoglucanes such as fractionated chitin and itsde-acetylated derivative chitosan, of microbial origin or isolated fromthe shells of arthropods such as crabs.

[0038] In preparing IMCs on the basis of PAGA according to the inventionthese three groups of substances can be combined to obtain requiredproperties of the final product.

[0039] In general it can be said that IMCs using substances from 1a and1b would preferably be used to prepare various types of highly absorbantbiocompatible dressing materials in the form of nonwovens, films,plasters, and pads. IMCs using the substances from 2 and 3 may serve asefficient haemostatic agents for internal applications in themicrofibrillar form, in the microdispersed form as dusting powders, inthe form of films, granules, tablets or non-woven textile-likestructures. Those preparations also display antiadhesive properties.

[0040] We have also found out that in the form of film-like cell culturematrices the latter IMCs incorporating PAGA and salts thereof asprepared according to PCT IE 98/00004 have a favourable effect on thegrowth of fibroblasts and keratinocytes.

[0041] While it is also possible to create IMCs using structuralscleroproteins of the collagen type as disclosed in WO 9800180A, it ispreferable to use the above mentioned groups of substances because ofthe possibility of contamination of the final product by telopeptides,viruses or pyrogens. Collagen can affect in an uncontrolled manner, theimmune response of the organism because formation of antibodies can beprovoked by any portion of the collagen structure even though the maindeterminants occur in the terminal regions of the collagenmacromolecule. Removal of telopeptides only partially solves theantigenicity problem (Michaeli et al: Science, 1969, 166, 1522).

[0042] By preparing IMCs according to the invention it is possible toessentially enhance properties of the originally preparedglucoronoglucanes such as 1,4 β PAGA. For instance an intermolecularcomplex salt of PAGA and gelatine in one single production step can beused to prepare final products in the form of a non woven, film,microdispersed granules, or dispersions. In contrast to collagen,suitably hydrolysed gelatine is well tolerated, has no toxicity or sideeffects and it is a much less costly raw material. We have found outthat this complex has very good haemostatic properties being about 40%higher than the original PAGA calcium sodium salt. This is despite thefact that the gelatine itself only displays a haemostatic effect afteran addition of thrombin [Schwartz S. I. et al.: Principles of Surgery,St. Louis: McGraw Hill Co, 1979, p. 122-123]. In this case theabsorption in the organism can be controlled by changing the compositionof the complex within the range from tens of hours to several months.This complex has a higher haemostatic efficiency and can be used as anembolisation or microembolisation product. It can also be used toprepare haemostatic layers of highly absorbent multi-layer dressings orresorbable plasters, though more costly polybren or protamines couldalso be applied.

[0043] An important advantage of these IMCs is the fact that thecompounds can be prepared within a single manufacturing operation usingthe hydrolytic process described in PCT IE 98/00004 which makes theseproducts cost effective.

[0044] These IMCs can further be modified by biologically active and/orbiologically acceptable substances. Because the IMCs prepared by thepresent procedure are either of a microdispersed or microfibrillarnature, the active substances tend to be bound uniformly and also areuniformly released in the organism without the need for other adjuvantssuch as microcrystalline waxes or stearates. However, the addition ofsuch adjuvants is not excluded.

[0045] Biologically active substances which can be incorporated into theIMC may involve, for instance, antibiotics carrying at least a weakpositive charge in the molecule such as cephalosporins (cephotaxin),aminoglycosides (neomycin, gentamycin, amikacin), penicillins(tikarcilin) or macrolides (erythromycin, clarithromycin) and the like.

[0046] In cases where the calcium/sodium salt of PAGA or its IMCcomplexes according to the invention are used as microembolisation orembolisation agents in regional chemotherapy of malign tumours, suitabletypes of cytostatics such as adriamycin or derivatives of1,4-diaminoanthrachinone can be incorporated. It is also possible to usethe IMCs as detaching ligands for platinum(II) based cytostatics.

[0047] Biologically acceptable substances used for modification of theIMCs include, for instance, glycerol and its polymers (polyglycerols);mono, di, and certain triglycerides; polyethyleneglycols;monopropyleneglycol; block copolymers of polyethyleneoxides andpolypropyleneoxides (Pluronic); starches; cyclodextrines;polyvinylalcohols; cellulose and its derivatives; in general, substancesthat, in the concentrations used, are not irritating or toxic for theliving organism while being capable of further optimising thephysicomechanical properties of the final product based on the IMCsaccording to the invention.

[0048] The invention will be more clearly understood from the followingexamples of polymer complexes of glucuronoglucanes.

EXAMPLE 1

[0049] Material:

[0050] long-fibre cotton—medicinal cotton wool oxidised by N_(x)O_(y)(proprietary)

[0051] C₆OOH 18.8% b/w

[0052] ash content <0.1% b/w

[0053] ΣC═O 0.6% b/w

[0054] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0055] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0056] demineralised water 2 μS

[0057] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0058] acid acetic anal.grade (Lachema, a.s. Neratovice)

[0059] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0060] N-HANCE 3000 guargumhydroxypropyltriammoniumchloride(Aqualon-Hercules)

[0061] Equipment:

[0062] mixer: bottom stirring, 150 litre (duplicator), stainless steelEXTRA S

[0063] vibrating screen: stainless steel, 150 mesh

[0064] rotary air pump: rotor diameter 150 mm

[0065] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0066] beaker: 5 litre

[0067] pH meter PICCOLO

[0068] thermocouple thermometer

[0069] Procedure:

[0070] 30 g of N-HANCE 3000 were placed into a 5 l beaker and 3 l ofdemineralised water 2 μS were added. The contents of the beaker wereintensely stirred for 30 minutes. The pH value was adjusted to less than4.5 by the addition of an acetic acid solution leading to a viscosityrise.

[0071] 60 l of demineralised water 2 μS were introduced into a mixer. 3kg of CaCl₂.6H₂O anal.grade were added and the contents heated up to atemperature of 50° C. with stirring. On dissolution of the calciumchloride the stirring was interrupted and 2.7 kg of the raw oxidisedcotton wool were introduced. The mixer was closed and the contents wereagitated for 120 seconds. The pH value of the contents was adjusted byaddition of a 20% solution of Na₂CO₃ to 6-6.5 and 13 kg of H₂O₂ 30% wereintroduced. The fibre suspension was slowly agitated for 10 minutes.Then the pH value was readjusted to 4.5-5.0 and the prepared viscoussolution of N-HANCE 3000 was introduced. The contents of the mixer werestirred intensely for 30 seconds. Subsequently 60 l of syntheticrectified ethanol conc. 98% were introduced into the mixer. 15 secondsafter adding the ethanol the contents of the mixer were transferred ontoa vibrating screen, and the supernatant liquid was filtered off. Thefiltration cake was redispersed in the mixer in 60 l of a mixture of 18l of synthetic rectified ethanol conc. 98% and 42 l of demineralisedwater 2 μS. The fibre suspension was filtered again on the vibratingscreen.

[0072] The isolated material thus prepared may further serve to preparefinal products of the nonwoven type via a wet or dry process.

[0073] Analysis: Ca content  4.0% b/w Na content  1.8% b/w Σ C═O content 0.0% b/w COOH content 20.7% b/w

EXAMPLE 2

[0074] Material:

[0075] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0076] C₆OOH 16.8% b/w

[0077] ash content <0.15% b/w

[0078] C═O 2.6% b/w

[0079] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0080] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0081] redistilled water (PhBs 1997)

[0082] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0083] isopropanol 99.9% (Neuberg Bretang)

[0084] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0085] gelatine (PhBs 1997)

[0086] Equipment:

[0087] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0088] sulphonation flask 1 litre

[0089] heater 1.5 kW

[0090] laboratory centrifuge: 4000 rpm

[0091] thermostated water bath

[0092] pH meter PICCOLO

[0093] glass thermometer

[0094] rotary vacuum dryer or hot-air dryer

[0095] Procedure:

[0096] Into a 1 litre sulphonation flask equipped with a turbostirrerand a heater, 400 ml of redistilled H₂O were placed, 15.73 g ofCaCl₂.6H₂O were added and on dissolution, 40.0 g of 20% Na₂CO₃ solutionwere introduced under stirring. Subsequently, 50 g of oxidised Linterswere added to the white emulsion formed and the contents were heated upto 95° C. with the stirring intensity set to a maximum. After 10minutes, 30 g of 30% H₂O₂ were added into the flask and the hydrolysiscontinued for another 10 minutes. The contents were then cooled down to60° C. on a water bath and the pH of the system was adjusted to a valueof 4.5-5.0 by the addition of a 20% solution of Na₂CO₃. A gelatinesolution (10 g of gelatine in 70 g of redistilled H₂O) warmed to 50° C.was added and left to react for another 20 minutes. The flask contentswere then cooled to 30° C. in a water bath and 626 ml of syntheticrectified ethanol conc. 98% were added gradually under intense stirring.The suspension of IMC thus formed was isolated using a laboratorycentrifuge. The supernatant liquid was filtered away and the cake wasredispersed into 250 ml of 50% ethanol. The system was centrifuged againand after the separation of the supernatant liquid, the IMC wasredispersed into 250 ml of synthetic rectified ethanol conc. 98% andalllowed stand for 4 hours. It was then centrifuged again, redispersedinto 99.9% isopropanol, and left to stand for a minimum of 10 hours at20° C. The gel formed was centrifuged and the product was dried in arotary vacuum dryer or a hot-air dryer.

[0097] The product can be used, for instance, for microembolisation, forpreparation of haemostatic dusting powders, for manufacture of polymerdrugs, e.g. based on cytostatics, or for preparation of sphericparticles for macroembolisation.

[0098] Analysis: content Ca  4.4% b/w content Na  2.7% b/w content Σ C═O 0.0% b/w content COOH 20.5% b/w content N  1.8% b/w

EXAMPLE 3

[0099] Material:

[0100] oxidised short-fibre cotton (Linters-Temming) proprietary)

[0101] C₆OOH 16.8% b/w

[0102] ash content <0.15% b/w

[0103] ΣC═O 2.6% b/w

[0104] NaOH anal.grade (Lachema, a.s. Neratovice)

[0105] redistilled water (PhBs 1997)

[0106] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0107] isopropanol 99.9% (Neuberg Bretang)

[0108] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0109] gelatine (PhBs 1997)

[0110] Equipment:

[0111] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0112] sulphonation flask 1 litre

[0113] heater 1.5 kW

[0114] laboratory centrifuge: 4000 rpm

[0115] thermostated water bath

[0116] pH meter PICCOLO

[0117] glass thermometer

[0118] rotary vacuum dryer or hot-air dryer

[0119] Procedure:

[0120] Into a 1 litre sulphonation flask equipped with a turbostirrerand a heater, 400 ml of redistilled H₂O were placed, and 8 g of NaOHwere added. On dissolution, 50 g of oxidised Linters were added, thecontents were heated up to 70° C. and the stirring intensity set to amaximum. After 20 minutes, 40 g of 30% H₂O₂ were added into the flask,the temperature was increased to 85° C., and maintained for another 10minutes. The contents were then cooled to 50° C. on a water bath andgelatine solution (10 g of gelatine in 70 g of redistilled H₂O) warmed50° C. was added to the hydrolysate. The temperature was decreased to25-30° C. and the pH of the system was checked and adjusted to a valueof 6.0-6.5. Subsequently, 626 ml of synthetic rectified ethanol conc.98% were added gradually under intense stirring. The suspension of IMCthus formed was isolated using a laboratory centrifuge. The supernatantliquid was filtered away and the cake was redispersed into 250 ml of 50%ethanol. The system was centrifuged and after the separation of thesupernatant liquid, the IMC was redispersed into 250 ml of syntheticrectified ethanol conc. 98% and left to stand for 4 hours. It was thencentrifuged, redispersed into 99.9% isopropanol, and allowed stand for aminimum of 10 hours at 20° C. The gel formed was centrifuged and theproduct was dried in a rotary vacuum dryer or a hot-air dryer.

[0121] The product can be used, for instance, for microembolisation, forpreparation of haemostatic dusting powders, for manufacture of polymerdrugs, e.g. based on cytostatics, or for preparation of sphericparticles for macroembolisation.

[0122] Analysis: Na content  3.8% b/w Σ C═O content  0.0% b/w COOHcontent 21.5% b/w N content  2.7% b/w

EXAMPLE 4

[0123] Material:

[0124] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0125] C₆OOH 16.8% b/w

[0126] ash content <0.15% b/w

[0127] ΣC═O 2.6% b/w

[0128] 20% solution NaCO₃ (Lachema, a.s. Neratovice)

[0129] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0130] redistilled water (PhBs 1997)

[0131] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0132] isopropanol 99.9% (Neuberg Bretang)

[0133] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0134] chitosan, degree of deacetylation 92% (Henkel)

[0135] Equipment:

[0136] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0137] sulphonation flask 1 litre

[0138] heater 1.5 kW

[0139] laboratory centrifuge: 4000 rpm

[0140] thermostated water bath

[0141] pH meter PICCOLO

[0142] glass thermometer

[0143] rotary vacuum dryer or hot-air dryer

[0144] Procedure:

[0145] Into a sulphonation flask, 250 ml redistilled H₂O were placed,and 5 g of NaOH were added. On dissolution, 25 g of oxidised Linterswere introduced under stirring, the temperature increased to 50° C. andthe stirring intensity set to a maximum. After hydrolysing for 15minutes, 35 g of 30% H₂O₂ were gradually added to the system and thetemperature was maintained at 50° C. for another 20 minutes. Thecontents were cooled to 30° C. and 400 g of highly viscous 5% solutionof chitosan were added. The flask contents were then intensely stirredfor another 10 minutes, and the pH of the system was adjusted by theaddition of NaOH to a value of 7.0. Subsequently 300 ml of syntheticrectified ethanol conc. 98% were added with stirring. The suspension ofIMC thus formed was isolated using a laboratory centrifuge. Thesupernatant liquid was filtered away and the cake was redispersed into250 ml of 50% ethanol. The system was centrifuged again and after theseparation of the supernatant liquid, the IMC was redispersed into 250ml of synthetic rectified ethanol conc. 98% and left to stand for 4hours. It was then centrifuged again, redispersed into 99.9%isopropanol, and left for a minimum of 10 hours at 20° C. The gel formedwas centrifuged and the product was dried in a rotary vacuum dryer or ahot-air dryer.

[0146] The product can be used, for instance, for microembolisation, forpreparation of haemostatic dusting powders, for manufacture of polymerdrugs, e.g. based on cytostatcs, or for preparation of spheric particlesfor macroembolisation.

[0147] Analysis: Na content  1.8% b/w Σ C═O content  0.0% b/w COOHcontent 10.4% b/w N content  2.8% b/w

EXAMPLE 5

[0148] Material:

[0149] oxidised short-fibre cotton (Linters-Terming) (proprietary)

[0150] C₆OOH 16.8% b/w

[0151] ash content <0.15% b/w

[0152] ΣC═O 2.6% b/w

[0153] NaOH anal.grade (Lachema, a.s. Neratovice)

[0154] HCl 39% anal.grade (Lachema, a.s. Neratovice)

[0155] redistilled water (PhBs 1997)

[0156] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0157] isopropanol 99.9% (Neuberg Bretang)

[0158] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0159] gelatine (PhBs 1997)

[0160] Ambroxol (H. Mack, Germany)

[0161] Equipment:

[0162] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0163] sulphonation flask 2 l

[0164] heater 1.5 kW

[0165] laboratory centrifuge: 4000 rpm

[0166] laboratory pin mill ALPINE (35 000 rpm)

[0167] thermostated water bath

[0168] pH meter PICCOLO

[0169] glass thermometer

[0170] rotary vacuum dryer or hot-air dryer

[0171] Procedure:

[0172] Into a sulphonation flask, 400 ml redistilled H₂O were placed,and 8 g of NaOH were added. On dissolution, 50 g of oxidised Linterswere introduced under stirring, the temperature increased to 70° C. andthe stirring intensity was set to a maximum. After hydrolysing for 20minutes, 40 g of 30% H₂O₂ were gradually added to the system and thetemperature was increased to, and maintained at, 85° C. for another 10minutes. The content were cooled down to 50° C. in a water bath, andgelatine solution (2 g of gelatine in 70 g of redistilled H₂O) warmed upto 50° C. was added to the hydrolysate. The temperature was decreased to25-30° C. and the pH of the system was checked and adjusted to a valueof 1.6-1.8 by addition of 39% HCl. Under intense stirring, a solution ofAmbroxol (25 g of ambroxolium hydrochloride in 500 ml of redistilledH₂O) was added gradually. After agitating for 5 minutes the pH value wasadjusted to 4.3-4.6 by adding 5% NaOH solution, and 626 ml of syntheticrectified ethanol conc. 98% were added under intense stirring. Thesuspension of Ambroxol containing IMC thus formed was isolated using alaboratory centrifuge. The supernatant liquid was filtered away and thecake was redispersed into, subsequently, 800 ml of 60% ethanol and 250ml of 98% ethanol, wherein it was let to stay for a minimum of 10 hours.The system was centrifuged again and the product was dried at 40° C. ina rotary vacuum dryer or a hot-air dryer. A white to slightly yellowishpowder was obtained and further desagglomerated on an Alpine pin mill.

[0173] The product serves for the preparation of a mucoregulatory drugwith a prolonged action.

[0174] Analysis: Na content  4.6% b/w Σ C═O content  0.0% b/w COOHcontent 14.8% b/w N content  1.9% b/w

EXAMPLE 6

[0175] Material:

[0176] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0177] C₆OOH 16.8% b/w

[0178] ash content <0.15% b/w

[0179] ΣC═O 2.6% b/w

[0180] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0181] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0182] redistilled water (PhBs 1997)

[0183] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0184] isopropanol 99.9% (Neuberg Bretang)

[0185] H₂O anal.grade 30% (Lachema, a.s. Neratovice)

[0186] gelatine (PhBs 1997)

[0187] gentamycin sulphate (MERCK)

[0188] Equipment:

[0189] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0190] sulphonation flask 2 litre

[0191] heater 1.5 kW

[0192] laboratory centrifuge: 4000 rpm

[0193] laboratory pin mill ALPINE (35 000 rpm)

[0194] thermostated water bath

[0195] pH meter PICCOLO

[0196] glass thermometer

[0197] hot-air dryer

[0198] lyophiliser (Leibold Heraus, Germany)

[0199] Procedure:

[0200] Into a 2 litre sulphonation flask equipped with a turbostirrerand a heater, 400 ml of redistilled H₂O were placed, 15.73 g ofCaCl₂.6H₂O were added and on dissolution, 40.0 g of 20% Na₂CO₃ solutionwere introduced under stirring. Subsequently, 50 g of oxidised Linterswere added to the white emulsion formed and the contents were heated upto 95° C. and the stirring intensity set to a maximum. After 10 minutes,30 g of 30% H₂O₂ were added into the flask and the hydrolysis wascontinued for another 10 minutes. The contents were then cooled down to60° C. on a water bath and the pH of the system was adjusted to a valueof 4.5-5.0 by addition of 20% solution of Na₂CO₃. A gelatine solution(10 g of gelatine in 70 g of redistilled H₂O) warmed up to 50° C. wasadded and let to react for another 20 minutes. The flask contents werethen cooled down to 30° C. in a water bath and 40 g of gentamycinsulphate in 600 ml of redistilled H₂O were added gradually within 10minutes. 626 ml of synthetic rectified ethanol conc. 98% were then addedgradually with intense stirring to the antibiotic containing IMCsuspension formed. The suspension of IMC thus formed was isolated usinga laboratory centrifuge. The supernatant liquid was filtered away andthe cake was redispersed into 250 ml of 50% ethanol. The system wascentrifuged and after the separation of the supernatant liquid, the IMCwas redispersed into 250 μm of synthetic rectified ethanol conc. 98% andleft for 4 hours. It was then centrifuged, redispersed into 99.9%isopropanol, and left for a minimum of 10 hours at 20° C. The gel formedwas centrifuged and the product was dried in a rotary vacuum dryer or ahot-air dryer.

[0201] The product can be used, for instance, for the manufacture of adusting powder or a powder spray for the treatment of infected wounds.

[0202] Analysis: Ca content 2.4% b/w Na content 1.6% b/w Σ C═O content0.0% b/w COOH content 9.6% b/w N content 2.7% b/w

EXAMPLE 7

[0203] Material:

[0204] long-fibre cotton—medicinal cotton wool oxidised by N_(x)O_(y)(proprietary)

[0205] C₆OOH 18.8% b/w

[0206] ash content <0.1% b/w

[0207] ΣC═O 0.6% b/w

[0208] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0209] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0210] demineralised water 2 μS

[0211] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0212] isopropanol 99.9% (Neuberg Bretang)

[0213] acid acetic anal.grade (Lachema, a.s. Neratovice)

[0214] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0215] N-HANCE 3000 guargumhydroxypropyltriammoniumchloride(Aqualon-Hercules)

[0216] polybren (hexadimethrindibromide) (FLUKA)

[0217] chlorhexidindigluconate

[0218] Equipment:

[0219] mixer: bottom stirring, 1501 (duplicator), stainless steel EXTRAS

[0220] vibrating screen: stainless steel, 150 mesh

[0221] rotary air pump: rotor diameter 150 mm

[0222] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0223] beaker: 5 litre

[0224] pH meter PICCOLO

[0225] thermocouple thermometer

[0226] Procedure:

[0227] 30 g of N-HANCE 3000 were placed into and 5 l beaker and 3 l ofdemineralised water 2 μS were added. Contents of the beaker were stirredintensely for 30 minutes. The pH value was adjusted to less than 4.5 bythe addition of an acetic acid solution leading to a viscosity rise.

[0228] 60 l of demineralised water 2 μS were introduced into a mixer.Then 3 kg of CaCl₂.6H₂O anal.grade were added and the contents heated upto a temperature of 50° C. under stirring. On dissolution of the calciumchloride the stirring was interrupted and 2.7 kg of the raw oxidisedcotton wool were introduced. The mixer was closed and the contents wereagitated for 120 seconds. Then the pH value of the contents was adjustedby the addition of a 20% solution of Na₂CO₃ to 6-6.5 and 13 kg of H₂O₂30% were introduced. The fibre suspension was slowly agitated for 10minutes. The pH value was readjusted to 4.5-5.0 and the prepared viscoussolution of N-HANCE 3000 was introduced. The contents of the mixer werestirred intensely for 30 seconds. A solution of 35 g of chlorhexidinedigluconate in 350 ml of demineralised water 2 μS was then introducedslowly within 10 minutes. Within another 10 minutes, a solution ofpolybren containing 120 g of polybren in 1000 ml of demineralised water2 μS was added. Subsequently 60 l of synthetic rectified ethanol conc.98% were introduced into the mixer. 15 seconds after adding the ethanol,the contents of the mixer were transferred onto a vibrating screen, andthe supernatant liquid was filtered off. The filtration cake wasredispersed in the mixer in 60 l of a mixture of 18 l of syntheticrectified ethanol conc. 98% and 42 l of demineralised water 2 μS. Thefibre suspension was filtered again on the vibrating screen.

[0229] The isolated material thus prepared may further serve to prepare,via a wet or dry process, final products of the non-woven type having anenhanced haemostatic activity and a bactericidal effect.

[0230] Analysis: Ca content  3.6% b/w Na content  1.9% b/w Σ C═O content 0.0% b/w COOH content 18.1% b/w N content 0.35% b/w

EXAMPLE 8

[0231] Material:

[0232] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0233] C₆OOH 16.8% b/w

[0234] ash content <0.15% b/w

[0235] ΣC═O 2.6% b/w

[0236] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0237] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0238] redistilled water (PhBs 1997)

[0239] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0240] isopropanol 99.9% (Neuberg Bretang)

[0241] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0242] Chitosan, degree of deacetylation 92% (Henkel)

[0243] Clarithromycin lactobionan (Abbott Laboratories, Italy)

[0244] Equipment:

[0245] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0246] sulphonation flask 1 litre

[0247] heater 1.5 kW

[0248] laboratory centrifuge: 4000 rpm

[0249] thermostated water bath

[0250] pH meter PICCOLO

[0251] glass thermometer

[0252] rotary vacuum dryer or hot-air dryer

[0253] dialysing bag (regenerated cellulose)

[0254] lyophiliser (Leybold Heraus, Germany)

[0255] laboratory pin mill ALPINE (35 000 rpm)

[0256] Procedure:

[0257] Into a sulphonation flask 250 ml redistilled H₂O were placed and5 g of, NaOH were added. On dissolution, 25 g of oxidised Linters wereintroduced under stirring, the temperature increased to 50° C. and thestirring intensity set to a maximum. After hydrolysing for 15 minutes,35 g of 30% H₂O₂ were gradually added to the system and the temperaturewas maintained at 50° C. for another 20 minutes. The content were cooleddown to 30° C. and 400 g of highly viscous 2% solution of chitosan,having a pH value of 3.5, were added. The flask contents were thenintensely stirred for another 10 minutes, and the pH of the system wasadjusted, by addition of NaOH, to a value of 7.0. During another 10minutes, a solution of clarithromycin (44 g of clarithromycin in 456 mlof redistilled H₂O) was introduced and the pH of the system was adjustedto a value of 7.0-7.5. Stirring was interrupted, the flask contents weretransferred into a dialysing bag and dialysed against water for 48hours. Subsequently the product was isolated by centrifugation,lyophilised, and disintegrated using the laboratory pin mill ALPINE.

[0258] The product can be used, for instance, to prepare tablets orgranules efficient against Helicobacter pylori occurring in thegastrointestinal tract.

[0259] Analysis: Na content  4.8% b/w Σ C═O content  0.0% b/w COOHcontent 18.8% b/w N content  0.7% b/w

EXAMPLE 9

[0260] Material:

[0261] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0262] C₆OOH 16.8% b/w

[0263] ash content <0.15% b/w

[0264] ΣC═O 2.6% b/w

[0265] NaOH anal.grade (Lachema, a.s. Neratovice)

[0266] redistilled water (PhBs 1997)

[0267] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0268] isopropanol 99.9% (Neuberg Bretang)

[0269] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0270] gelatine (PhBs 1997)

[0271] Bi(NO₃).5H₂O (MERCK)

[0272] Equipment:

[0273] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0274] sulphonation flask 2 litre

[0275] heater 1.5 kW

[0276] laboratory centrifuge: 4000 rpm

[0277] thermostated water bath

[0278] pH meter PICCOLO

[0279] glass thermometer

[0280] rotary vacuum dryer or hot-air dryer

[0281] Procedure:

[0282] Into a sulphonation flask 400 ml redistilled H₂O were placed and8 g of NaOH were added. On dissolution, 50 g of oxidised Linters wereintroduced under stirring, the temperature increased to 70° C. and thestirring intensity was set to a maximum. After hydrolysing for 20minutes, 40 g of 30% H₂O₂ were gradually added to the system and thetemperature was increased to, and maintained at, 85° C. for another 10minutes. The contents were cooled down to 50° C. in a water bath, and agelatine solution (0.5 g of gelatine in 50 ml of redistilled H₂O) warmedup to 50° C. was added to the hydrolysate. The temperature was decreasedto 25-30° C. and the pH of the system was checked and adjusted to avalue of 1.6-1.8 by addition of 39% HCl. A freshly prepared solution ofBiNO₃ (54 g of BiNO₃.5H₂O in 746 ml of H₂O) was introduced and thetemperature maintained for another 15 minutes. The temperature wasdecreased to 25-30° C. and the pH of the system was checked andreadjusted to a value of 5.5-6.0. 626 ml of 1 synthetic rectifiedethanol conc. 98% were then added gradually with intense stirring. TheBiO⁺ containing IMC suspension thus formed was isolated using alaboratory centrifuge. The supernatant liquid was filtered away and thecake was redispersed into 250 ml of 50% ethanol. The system wascentrifuged again and after the separation of the supernatant liquid,the IMC was redispersed into 250 ml of synthetic rectified ethanol conc.98% and left for a minimum of 4 hours. It was then centrifuged again,redispersed into 99.9% isopropanol, and left for a minimum of 10 hoursat 20° C. The suspension formed was then centrifuged again and theproduct was dried in a rotary vacuum dryer or a hot-air dryer.

[0283] The product can be used, for instance, to prepare dusting powdersfor wound treatment or tablets for treatment of gastrointestinal tractmalfunctions.

[0284] Analysis: Na content  1.9% b/w Σ C═O content  0.0% b/w COOHcontent 20.0% b/w N content <0.3% b/w Bi content  4.7% b/w

EXAMPLE 10

[0285] Material:

[0286] oxidised short-fibre cotton (Linters-Temming) (proprietary)

[0287] C₆₀OH 16.8% b/w

[0288] ash content <0.15% b/w

[0289] ΣC═O 2.6% b/w

[0290] 20% solution Na₂CO₃ (Lachema, a.s. Neratovice)

[0291] CaCl₂.6H₂O anal.grade (Lachema, a.s. Neratovice)

[0292] redistilled water (PhBs 1997)

[0293] ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov,a.s.)

[0294] isopropanol 99.9% (Neuberg Bretang)

[0295] H₂O₂ anal.grade 30% (Lachema, a.s. Neratovice)

[0296] gelatine (PhBs 1997)

[0297] cimetidine hydrochloride (SPOFA)

[0298] Equipment:

[0299] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0300] sulphonation flask 2 litre

[0301] heater 1.5 kW

[0302] laboratory centrifuge: 4000 rpm

[0303] thermostated water bath

[0304] pH meter PICCOLO

[0305] glass thermometer

[0306] rotary vacuum dryer or hot-air dryer

[0307] Procedure:

[0308] Into a 1 l sulphonation flask equipped with a turbostirrer and aheater, 400 ml of redistilled H₂O were placed. 15.73 g of CaCl₂.6H₂Owere added and on dissolution 40.0 g of 20% Na₂CO₃ solution wereintroduced with stirring. 50 g of oxidised Linters were added to thewhite emulsion formed and the contents were heated up to 95° C. and thestirring intensity set to a maximum. After 10 minutes, 30 g of 30% H₂O₂were added into the flask and the hydrolysis was continued for another10 minutes. The contents were then cooled down to 60° C. on a water bathand the pH of the system was adjusted to a value of 4.5-5.0 by additionof 20% solution of Na₂CO₃. A gelatine solution (10 g of gelatine in 70 gof redistilled H₂O) warmed up to 50° C. was added and allowed react foranother 20 minutes. The flask contents were then cooled down to 30° C.in a water bath and a solution of cimetidine (36 g of cimetidinehydrochloride in 400 ml of redistilled H₂O) were added with intensestirring. The contents were intensely agitated for 10 minutes and 800 mlof synthetic rectified ethanol conc. 98% were added gradually. Thesuspension of IMC thus formed was isolated using a laboratorycentrifuge. The supernatant liquid was filtered away and the cake wasredispersed into 250 ml of 50% ethanol. The system was centrifuged andafter separation of the supernatant liquid, the IMC was redispersed into250 ml of synthetic rectified ethanol conc. 98% and left for 4 hours. Itwas then centrifuged again, redispersed into 99.9% isopropanol, and leftfor a minimum of 10 hours at 20° C. The gel formed was centrifuged againand the product was dried in a rotary vacuum dryer or a hot-air dryer.

[0309] The product can be used, for instance, to manufacture tablets orgranulates for the treatment of the gastrointestinal tract or othernon-malignant ulcerations.

[0310] Analysis: Ca content  4.4% b/w Na content  2.7% b/w Σ C═O content 0.0% b/w COOH content 20.5% b/w N content  2.1% b/w

EXAMPLE 11

[0311] Material:

[0312] IMC-microdispersed oxidised cellulose (MDOC) complex (as perabove Example 2)

[0313] [(2S;2R)-3-amino-2-hydroxy-4-phenylbutenoyl]-L-leucin (Bestatin)(Boehringer Mannheim, Germany)

[0314] redistilled water (PhBs 1997)

[0315] methanol, conc. anal.grade (Chemopetrol Litvinov, a.s.)

[0316] diethylether (Lachema, a.s. Neratovice)

[0317] Equipment:

[0318] turbostirrer: ULTRA TURAX (Janke-Kunkel)

[0319] sulphonation flask 2 l

[0320] laboratory centrifuge: 4000 rpm

[0321] hot-air dryer

[0322] Procedure:

[0323] The IMC-MDOC complex as prepared in Example 2 above wasredispersed into redistilled water in a sulphonation flask using aturbostirrer. A solution of Bestatin in methanol was added to the flaskin an amount sufficient to yield a 10% b/w concentration of Bestatin inthe resulting Bestatin-gelatine-MDOC complex. After thoroughhomogenisation, the suspension formed was isolated by centrifugation.The supernatant liquid was filtered away and the filtration cake wasredispersed into concentrated methanol, centrifuged, redispersed indiethylether, and after being left for 1 hour, it was dried in a hot-airdryer.

[0324] The product, a microdispersed form of a Bestatin-gelatine-MDOCcomplex, can be used, for instance, to prepare microembolisation agentsused in regional chemotherapy of malignant tumours or flat dressingstructures for wound treatment.

[0325] The following are application examples illustrating some of theuses of the products produced in examples 1 to 11.

EXAMPLE A Preparation of Tablets and Pellets from IMC-MDOC Complex

[0326] MDOC=Microdispersed Oxidised cellulose

[0327] Material:

[0328] IMC-MDOC complex—see Example 2

[0329] magnesium stearate (SIGMA)

[0330] ascorbic acid (MERCK)

[0331] α-tocoferol acetate (Slovakofarma HIohovec)

[0332] ethanol synthetic rectified (Chemopetrol Litvinov, a.s.)

[0333] Equipment:

[0334] tabletting machine (KORSCH EK 0, Berlin)

[0335] blender (Nautamix 300)

[0336] counter-flow drier BINDER

[0337] Procedure:

[0338] 10 kg of IMC-MDOC complex of composition according to Example 2were placed into the blender, and 660 g of micronised ascorbic acid,1660 g of α-tocoferol acetate emulgated in 2500 ml of ethanol, and 1000g of magnesium stearate were added. The mixture was homogenised for 3hours. It was then dried in a counter-flow drier at a temperature of 50°C. until ethanol was removed.

[0339] 100 g of the resulting dry powder were introduced into thetabletting machine, and the tabletting force was set at a value of 7 kN.

[0340] Result:

[0341] The tablets prepared were smooth and well cohering and had aweight of 0.5 g. Disintegration rate of the tablets in a saline F1/1 was17 minutes at 20° C., and 8 minutes at 37° C.

APPLICATION EXAMPLE

[0342] Patient aged 57, displaying an increased cholesterol content inblood was treated by MDOC tablets administered orally for 50 days, at adose of 6 tablets daily. After the treatment both LDL content and totalcholesterol content were significantly reduced. Blood analysis: beforetreatment after treatment Total Cholesterol 7.70 mmol/l 5.70 mmol/l HDL1.16 mmol/l 1.30 mmol/l LDL 4.40 mmol/l 3.30 mmol/l Triacylglycerols1.81 mmol/l 1.80 mmol/l

EXAMPLE B Preparation of Tablets and Pellets with IMC-MDOC ComplexContaining Clarithromycin

[0343] Material:

[0344] IMC-MDOC complex—see Example 8

[0345] MDOC, particle size 0.1-2.0 μm, specific surface area 86 m², COOHgroup content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/w

[0346] IMC-MDOC complex containing BiO⁺—see Example 9

[0347] Equipment:

[0348] laboratory mixer, bottom agitated, 4000 rpm

[0349] tabletting machine (KORSCH EK 0, Berlin)

[0350] Procedure:

[0351] 9.5 g of IMC-MDOC containing clarithromycin were placed into themixer, and 12.0 g of BiO⁺ salt and 78.5 g of MDOC were added. The vesselwas closed, the agitation set on, and the contents were homogenised for60 seconds. The homogenised mixture was then transferred to the storagevessel of the tabletting machine, and the tabletting force was set to avalue of 7.5 kN.

[0352] Result:

[0353] The tablets prepared were smooth and cohering and had a weight of0.5 g. Disintegration rate of the tablets in a saline F1/1 was 12minutes at 20° C., and 5 minutes at 37° C.

[0354] Indication:

[0355] The tablets are indicated for treatment of gastric ulcers. MDOCsuppresses formation of the stomach acidity, adjust the pH value of theenvironment, and protects the mucous membranes by forming a gel layer.BiO⁺ acts as a mild astringens. Clarithromycin depresses the growth ofHelicobacter pylori beyond pathologic limits.

EXAMPLE C Preparation of Tablets and Pellets with IMC-MDOC ComplexContaining Ambroxol

[0356] Material:

[0357] MDOC, particle size 0.1-2.0 μm, specific surface area 86 m², COOHgroup content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/w

[0358] IMC-MDOC complex containing Ambroxol—see Example 5

[0359] microcrystalline cellulose (SIGMA)

[0360] hydroxypropylcellulose (Natrosol HHR 250)

[0361] magnesium stearate (SIGMA)

[0362] Macrogol 400 (SIGMA)

[0363] Equipment:

[0364] laboratory mixer, bottom agitated, 4000 rpm

[0365] tabletting machine (KORSCH EK 0, Berlin)

[0366] Procedure:

[0367] 43.0 g of MDOC, 42.0 g of IMC-MDOC containing ambroxol, 10.0 g ofmicrocrystalline cellulose, 2.0 g of magnesium stearate, 1.0 g ofMacrogolu 400, and 2.0 g of Natrosol HHR250 were introduced into themixer. The vessel was closed, agitation (4000 rpm) started and thecontents were homogenised for 120 seconds. The homogenised mixture wasthen transferred to the storage vessel of the tabletting machine and thetabletting force was set at a value of 5.0 kN.

[0368] Result:

[0369] The tablets prepared were smooth and cohering and had a weight of0.5 g. Disintegration rate of the tablets in a saline F1/1 was 10minutes at 20° C., and 6 minutes at 37° C.

[0370] Indication:

[0371] Acute and chronic respiratory diseases involving formation ofdense mucus (acute bronchitis, bronchial asthma), ease of mucusdissolution in rhinofaryngitis. In testing on volunteers at a dosagerate of 3 tablets per day, ambroxol could still be detected in the urineat Day 8 after administration.

EXAMPLE D Preparation of Tablets and Pellets with IMC-MDOC ComplexContaining Cimetidine

[0372] Material:

[0373] MDOC, particle size 0.1-2.0 μm, specific surface area 86 m², COOHgroup content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/w

[0374] IMC-MDOC complex containing cimetidine—see Example 10 Macrogol400 (SIGMA)

[0375] Equipment:

[0376] laboratory mixer, bottom agitated, 4000 rpm

[0377] tabletting machine (KORSCH EK 0, Berlin)

[0378] Procedure:

[0379] 63.0 g of IMC-MDOC containing cimetidine, 32.0 g of MDOC and 5.0g of Macrogolu 400 were introduced into the mixer. The vessel wasclosed, the agitation set on, and the contents were homogenised for 60seconds. The homogenised mixture was then transferred to the storagevessel of the tabletting machine, and the tabletting force was set to avalue of 7.5% N.

[0380] Result:

[0381] The tablets prepared were smooth and well cohering and had aweight of 1.0 g. Disintegration rate of the tablets in a saline F1/1 was8 minutes at 20° C., and 6 minutes at 37° C.

[0382] Indication:

[0383] The tablets are indicated for treatment of gastric ulcers. MDOCsuppresses formation of the stomach acidity, adjust the pH value of theenvironment, and protects the mucous membranes by forming a gel layer.BiO⁺ acts as a mild astringens. Cimetidine suppresses both basal andsimulated secretion of the stomach acid.

EXAMPLE E Preparation of Rectal Suppositories from IMC-MDOC BiO⁺ Complexcontaining aminophenazon and Allobarbital

[0384] Material:

[0385]Adeps neutralis (WERBA)

[0386]Oleum cacao (WERBA)

[0387] IMC-MDOC complex containing BiO⁺—see Example 9

[0388] Aminophenazonum (SPOFA)

[0389] Allobarbitalum (SPOFA)

[0390] Equipment:

[0391] stainless melting tank, agitated, volume 1000 ml, input power 600W

[0392] movable support carrying a shaped blister foil

[0393] Procedure:

[0394] 282.6 g of Adeps neutralis and 122.6 g of Oleum cacao wereintroduced into the melting tank. The contents were heated up to atemperature of 75° C. On melting, 16 g of Allobarbitalum, 117.3 g ofAminophenozonum and 61.33 g of IMC-MDOC complex containing BiO⁺ weregradually added under permanent agitation. After appropriatehomogenisation, the mass was cast into a shaped blister foil serving,when cooled down, as the suppository packaging.

[0395] Result:

[0396] Suppository of 8 mm diameter, 20 mm length, conical shape, weight2.25 g.

[0397] Indication:

[0398] Combined suppositories having antihaemorroidal andanalgetic/antipyretic effects.

EXAMPLE F Preparation of Vaginal Suppositories from IMC-MDOC ComplexContaining Gelatine, nitrofurantoin and Chlorohexidine

[0399] Material:

[0400] IMC-MDOC complex—see Example 2

[0401] gelatina animalis (SIGMA)

[0402] 1,2-monopropylenglykol (SIGMA)

[0403] glycerol, medicinal (MERCK)

[0404] nitrofurantoinum (SPOFA) broad spectrum anti-microbial andanti-inflammatory

[0405] chlorohexidine digluconate (FEROSAN)—local bacteriocideredistilled H₂O

[0406] Equipment:

[0407] stainless melting tank, agitated, volume 1000 ml, input power 600W

[0408] movable support carrying a shaped blister foil

[0409] Procedure:

[0410] 78 g of redistilled H₂O, 240 g of medicinal glycerol, 30 g of1,2-MPG were introduced into the melting tank and the mixture was heatedup to a temperature of 75° C. On melting, 30 g of nitroflurantoinu and30 g of chlorohexidine were gradually added under agitation, and themixture was agitated for another 15 minutes. Subsequently, 102 g ofgelatine animalis were introduced and, after appropriate homogenisation,90 g of IMC-MDOC complex were added. The resulting mixture was agitatedfor another 15 minutes and then the mass was cast into a shaped blisterfoil serving, when cooled down, as the suppository packaging.

[0411] Result:

[0412] Suppository of 8 mm diameter, 17 mm length, cylindrical shape,weight 2.0 g.

[0413] Indication:

[0414] Vaginal suppositories for use in treatment of urinary tractinfections due to both grampositive and gramnegative bacterias,displaying a prolonged effect. The IMC-MDOC present serves to protectthe vaginal mucous tissue and to create a natural microenvironmentsimilar to the action of lactic acid.

EXAMPLE G Preparation of Dental Pins from IMC-MDOC Complex Containingbactericidal Agent

[0415] Material:

[0416] IMC-MDOC complex—see Example 2

[0417] chlorhexidine digluconate (FEROSAN)

[0418] ethanol synthetic rectified 98%

[0419] Equipment:

[0420] laboratory mixer 4000 rpm

[0421] tabletting machine (KORSCH EK 0, Berlin)

[0422] Procedure:

[0423] 100 g of IMC-MDOC complex prepared according to Example 2 wereplaced into the mixer and a solution of 1.6 g of chlorohexidinedigluconate in 20 g of ethanol was added under stirring. The mixture washomogenised for 120 seconds, and then introduced into the tablettingmachine equipped with a set of special shaped moulds, and the tablettingforce was set at a value of 5 kN.

[0424] Result:

[0425] Dental pins of a cone frustrum shape, 15 mm in height and 7 mm inbase diameter, with lateral grooves to facilitate grasping the pin withtweezers.

[0426] Indication:

[0427] Treatment of massive postextractional bleeding with simultaneousadministration of a bactericidal agent.

EXAMPLE H Preparation of Dental Pins from IMC-MDOC Complex withAntimicrobial Agent

[0428] Material:

[0429] IMC-MDOC complex containing chitosan—see Example 4

[0430] MDOC, particle size 0.1-2.0 μm, specific surface area 86 m²/g,COOH group content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/w

[0431] polyvinylpyrrolidone-iodine complex PVP-I micronised (ISP-USA)

[0432] Equipment:

[0433] laboratory mixer 4000 rpm

[0434] tabletting machine (KORSCH EK 0, Berlin)

[0435] Procedure:

[0436] 50 g of IMC-MDOC complex, 49 g of MDOC and 1 g of PVP-I complexwere placed into the mixer. The mixture was homogenised for 120 seconds,and then introduced into the tabletting machine equipped with a set ofspecial shaped moulds, and the tabletting force was set at a value of 5kN.

[0437] Result:

[0438] Dental pins of a cone frustrum shape, 15 mm in height and 7 mm inbase diameter, with lateral grooves to facilitate grasping the pin withtweezers.

[0439] Indication:

[0440] Treatment of massive postextractional bleeding with simulataneousadministration of an antimicrobial agent.

EXAMPLE I Preparation of Granules from IMC-MDOC Complex Containing

[0441] Material:

[0442] IMC-MDOC complex—see Example 8

[0443] MDOC, particle size 0.1-2.0 μm, specific surface area 86 m²/g,COOH group content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/wIMC-MDOC complex containing BiO⁺—see Example 9

[0444] ethanol synthetic rectified 98%

[0445] redistilled H₂O

[0446] Equipment:

[0447] set of vibrating screens with mesh size 100, 150, 200, 250, 350,500 μm

[0448] mixer, bottom agitated, vessel size 1000 ml, 8000 rpm, equippedwith a nozzle for inlet of the granulation medium counter-flow drierBINDER

[0449] Procedure:

[0450] 100 g of MDOC were placed into the mixer, the mixer was closedand the agitation switched on. A mist of 88% aqueous solution of ethanolwas gradually injected into the mixer at a rate of 10 g/45 seconds. Thegranulate formed was transferred to the counter-flow drier and dried ata temperature of 45° C. until the humidity content was reduced below 6%b/w. The dried granules were sieve- screened using the set of vibratingscreens. The individual fractions were packaged into glass vials inamounts of 0.5-2.0 g each as required. The preparation was sterilised byy irradiation with a dose of 25 kGy.

[0451] Indication:

[0452] The granules can be used in the treatment of gastric ulcers. MDOCsuppresses formation of the stomach acidity, adjust the pH value of theenvironment, and protects the mucous membranes by forming a gel layer.BiO⁺ acts as a mild astringens. Clarithromycin depresses the growth ofHelicobacter pylori beyond pathologic limits.

EXAMPLE J Preparation of Granules from IC-MDOC Complex

[0453] Material:

[0454] IMC-MDOC complex—see Example 2

[0455] Equipment:

[0456] set of vibrating screens with mesh size 100, 150, 200, 250, 350,500 μm

[0457] mixer, bottom agitated vessel size 1000 ml, 8000 rpm, equippedwith a nozzle for inlet of the granulation medium counter-flow drierBINDER

[0458] Procedure:

[0459] 100 g of MDOC were placed into the mixer, the mixer was closedand the agitation switched on. Saturated water vapour was graduallyinjected into the mixer at a rate of 10 g/45 seconds. The granulateformed was transferred to the counter-flow drier and dried at atemperature of 45° C. until the humidity content was reduced below 6%b/w. The dried granules were sieve-screened using the set of vibratingscreens. The individual fractions were packaged into glass vials inamounts of 0.5-2.0 g each as required. The preparation was sterilised byy irradiation with a dose of 25 kGy.

[0460] Indication:

[0461] The product may be used as a) an embolisation agent, or b) anantilipemicum.

EXAMPLE K Preparation of granules from IMC-MDOC Complex ContainingAntimicrobial Agent

[0462] Material:

[0463] IMC-MDOC complex—see Example 2

[0464] polyvinylpyfrolidone-iodine PVP-I complex micronised (ISP-USA)

[0465] 1,2-monopropyleneglycol (MERCK)

[0466] redistilled H₂O

[0467] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)

[0468] Equipment:

[0469] set of vibrating screens with mesh size 100, 150, 200, 250, 350,500 μm

[0470] mixer, bottom agitated, vessel size 1000 ml, 8000 rpm, equippedwith a nozzle for inlet of the granulation medium counter-flow drierBINDER

[0471] Procedure:

[0472] 90 g of IMC-MDOC complex, 5 g of PVP-I complex and 5 g of 1,2-MPGwere placed into the mixer, the mixer was closed and the agitationswitched on. A mist of 88% aqueous solution of ethanol was graduallyinjected into the mixer at a rate of 10 g/50 seconds. The granulateformed was transferred to the counter-flow drier and dried at atemperature of 45° C. until the humidity content was reduced below 6%b/w. The dried granules were sieve-screened using the set of vibratingscreens. The fraction below 100 μm was used to prepare a dusting powder.The higher fractions were packaged into glass vials in amounts of0.5-2.0 g each as required.

[0473] Indication:

[0474] Haemostatic preparation with antimicrobial and antiviral effect(powder spray, dusting powder).

EXAMPLE L Preparation of Microspheres from IMC-MDOC Complex ContainingMitoxanthron

[0475] Material:

[0476] IMC-MDOC complex—see Example 3

[0477]1,4-bis-2-(−2-hydroxyethylamino-ethylamino-)5,8-dihydroxyantrachinon(mitoxanthron) (Aliachem a.s.)

[0478] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)redistilled H₂O

[0479] Equipment:

[0480] turbostirrer ULTRA TURAX (Janke-Kunkel)

[0481] sulphonation flask 1 l

[0482] beaker 250 ml

[0483] set of vibrating screens with mesh size 100, 150, 200, 250, 350,500 μm

[0484] counter-flow drier BINDER

[0485] vial 10 ml

[0486] injection syringe 25 ml

[0487] Procedure:

[0488] 80 g of redistilled water and 20 g of IMC-MDOC complex wereintroduced into the beaker, and the complex was dispersed using theturbostirrer to obtain a colloidal solution thereof.

[0489] 495 ml of 98% ethanol was placed into the sulphonation flask. 1.0g of mitoxanthron hydrochloride was placed into the 10 ml vial anddissolved in 5 g of redistilled water. The solution was then transferredinto the sulphonation flask with ethanol under stirring.

[0490] The colloidal solution of IMC-MDOC complex was then graduallyintroduced into the mitoxanthron solution by being dropped, via theinjection syringe, at a rate of 20 drops per minute into thesulphonation flask. The microspheres were isolated by filtration fromthe supernatant liquid, cautiously redispersed into 250 ml of 98%ethanol and allowed to stay for 4 hours. The ethanol was then removed byfiltration and the microspheres were dried in the counter-flow drier ata temperature of 40° C. until the humidity content was reduced below 3%b/w. The dry microspheres containing 50 mg of mitoxanthron per 1 g weresieve-screened using the set of vibrating screens, and packaged intoglass vials in amounts of 0.5 g each.

[0491] Indication:

[0492] Intraarterial (regional) chemotherapy of malignant tumours wheremitoxanthron is indicated.

EXAMPLE M Preparation of Microspheres from IMC-MDOC Complex ContainingMitoxanthron

[0493] Material:

[0494] MDOC (Ca/Na salt of PAGA), particle size 0.1-2.0 μm, specificsurface area 86 m²/g, COOH group content 22.2% b/w, Ca content 4.2% b/w,Na content 3.8% b/w

[0495] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)

[0496] redistilled H₂O

[0497] 1,2-monopropyleneglycol (Sigma)

[0498] sorbitol (Sigma)

[0499] isopropanol (Sigma)

[0500] Equipment:

[0501] propeller stirrer, 50 rpm

[0502] sulphonation flask 1 l

[0503] beaker 250 ml

[0504] set of vibrating screens with mesh size 100, 150, 200, 250, 350,500 μm

[0505] counter-flow drier BINDER

[0506] injection syringe 25 ml

[0507] Procedure:

[0508] 10 g of MDOC Ca/Na salt and 90 g of redistilled H₂O wereintroduced into the beaker, and dispersed using the propeller stirrer toobtain a colloidal solution.

[0509] A cogulating solution was prepared by dissolving 25 g of sorbitoland 25 g of monopropyleneglycol in 450 ml of 98% ethanol placed in thesulphonation flask. 1.0 g of mitoxanthron hydrochloride was placed intothe 10 ml vial and dissolved in 5 g of redistilled water. The solutionwas then transferred into the sulphonation flask with ethanol understirring.

[0510] The colloidal solution of MDOC was then gradually introduced intothe sulphonation flask by being dropped, via the injection syringe, at arate of 10 drops per minute. The microspheres were isolated from thecoagulating bath by decantation, 250 ml of isopropanol were added andthe microspheres were allowed to stay for 8 hours. The isopropanol wasthen removed by filtration and the microspheres were dried in thecounter-flow drier at a temperature of 40° C. until the humidity contentwas reduced below 3% b/w. The dry microspheres were sieve-screened usingthe set of vibrating screens, and packaged into glass vials in amountsof 0.5 g each.

[0511] Indication:

[0512] Microembolisation agent to achieve tissue necrotisation, e.g. ingynecological treatment of non-malignant tumours.

EXAMPLE N Preparation of Rigid Foams from IMC-MDOC Complex ContainingGelatine

[0513] Material:

[0514] IMC-MDOC complex —see Example 3

[0515] 1,2-dihydroxypropane (Sigma)

[0516] gelatine, hydrolysed (Infusia, a.s.)

[0517] glycerol, medicinal (PhBs 1997)

[0518] redistilled H₂O

[0519] Equipment:

[0520] turbostirrer ULTRA TURAX (Janke-Kunkel)

[0521] sulphonation flask 1 l

[0522] beaker 250 ml

[0523] lyophiliser

[0524] Procedure:

[0525] 400 g IMC-MDOC complex, 100 g of gelatine, 100 g of1,2-dihydroxypropane, 500 ml of redistilled water and 100 g of glycerolwere introduced into the sulphonation flask. The mixture was heated upto 70° C. and homogenised using the propeller stirrer. Thereafter, themixture was injected into suitably shaped moulds. After cooling down toroom temperature, the moulds have been placed into the lyophiliser andthe mass lyophilised. Tampons of the required shape were obtained in theform of a rigid flexible foam.

[0526] Indication:

[0527] Suitable for use as biocompatible and fully resorbable nasaltampons.

Example O PREPARATION of Rigid Foams from IMC-MDOC Complex containingChitosan

[0528] Material:

[0529] IMC-MDOC complex—see Example 3

[0530] 1,2-dihydroxypropane (Sigma)

[0531] gelatine, hydrolysed (Infusia, a.s.)

[0532] glutaraldehyde (Sigma)

[0533] chitosan, degree of deacetylation 92% (Henkel)

[0534] glycerol, medicinal (PhBs 1997)

[0535] redistilled H₂O

[0536] Equipment:

[0537] turbostirrer ULTRA TURAX (Janke-Kunkel)

[0538] sulphonation flask 1 l

[0539] beaker 250 ml

[0540] lyophiliser

[0541] Procedure:

[0542] 400 g FMC-MDOC complex, 100 g of gelatine, 100 g of1,2-dihydroxypropane, 500 ml of redistilled water and 100 g of glycerolwere introduced into the sulphonation flask. The mixture was heated upto 70° C. and homogenised using the propeller stirrer. Subsequently, 20g of chitosan were added, and the mixture was homogenised for another 5minutes, Thereafter, 200 g of glutaraldehyde were added and the mixturewas maintained 70° C. until the viscosity attained the value of 500mPas. The mixture was then injected into suitably shaped moulds. Aftercooling down to room temperature, the moulds have been placed into thelyophiliser and the mass was lyophilised. Foamed sheets of the requiredshape consisting of an insoluble, highly absorbing, crosslinked foamwere obtained.

[0543] Indication:

[0544] Suitable for use as inner absorbing layers of biocompatible padsand plasters.

EXAMPLE P Preparation of Microspheres from IMC-MDOC Complex ContainingPlatinum(II) Compounds

[0545] Material:

[0546] MDOC (Ca/Na salt of PAGA), particle size 0.1-2.0 μm, specificsurface area 86 m²/g, COOH group content 22.2% b/w, Ca content 4.2% b/w,Na content 3.8% b/w

[0547] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)

[0548] redistilled H₂O

[0549] 1,2-dihydroxypropane (Sigma)

[0550] polyacrylarmide, 50% aqueous solution (Aldrich)

[0551] glycerol, medicinal (PhBs 1997)

[0552] Equipment:

[0553] laboratory mixer, bottom agitated, 4000 rpm

[0554] sulphonation flask 1 l

[0555] injection syringe 25 ml

[0556] Procedure:

[0557] A colloidal aqueous solution of an MDOC-chitosan-polyacrylamidecomplex containing 30% b/w of MDOC Ca/Na salt was dropped, via theinjection syringe at a rate of 10 drops per minute, into aethanol/glycerol/water system containing salts of bivalent platinum withtwo ammonia (NH₃) ligands. The microspheres formed, contained(NH₃)₂Pt(II) groups, were isolated from the coagulating bath bydecantation, washed with concentrated ethanol, and vacuum dried at 25°C.

[0558] Indication:

[0559] Intraarterial (regional) chemotherapy of malignant tumours wherediamoplatinum(II) complexes are indicated.

EXAMPLE Q Preparation of Rigid Foams from IMC-MDOC Complex ContainingChitosan and Bestatin

[0560] Material:

[0561] IMC-MDOC bestatin complex—see Example 11

[0562] chitosan, degree of deacetylation 92% (Henkel)

[0563] polyacrylamide, 50% aqueous solution (Aldrich)

[0564] glycerol, medicinal (PhBs 1997)

[0565] redistilled H₂O

[0566] Equipment:

[0567] turbostirrer ULTRA TURAX (Janke-Kunkel)

[0568] sulphonation flask 1 l

[0569] laboratory heater

[0570] counter-flow drier BINDER

[0571] Procedure:

[0572] Bestatin containing IMC-MDOC complex as prepared according toExample 11, glycerol, 25% aqueous solution of polyacrylamide, 3%solution of chitosan in acetic acid solution, and redistilled water wereplaced into the sulphonation flask in amounts such that the glycerolcontent in the system attains 30% b/w and that of the IMC-MDOC complexattains 0.1% b/w. The mixture was toroughly homogenised for 5 minutesusing the turbostirrer, and n-pentane in an amount of 3%, calculated onthe total volume basis, was added and dispersed into the system.Thereafter, the mixture was injected into suitably shaped moulds anddried to obtain flexible foamed sheets.

[0573] Indication:

[0574] Suitable for use in preparation of embolisation agents, plastersand similar products.

EXAMPLE R Preparation of Flat Textile-Like structures Containing MDOCand IMC-MDOC Complex with Bestatin

[0575] Material:

[0576] cotton dressing pad

[0577] MDOC (Ca/Na salt of PAGA), particle size 0.1-2.0 μm, specificsurface area 86 m²/g, COOH group content 22.2% b/w, Ca content 4.2% b/w,Na content 3.8% b/w

[0578] IMC-MDOC bestatin complex—see Example 11

[0579] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)

[0580] demineralised water 2 μS

[0581] Equipment:

[0582] continuous spray-coating equipment

[0583] Procedure:

[0584] A dispersion of MDOC Ca/Na containing 10% b/w IMC-MDOC bestatincomplex prepared by the procedure according to Example 11 in 88.5%aqueous solution of ethanol was prepared within the storage tank of thespray coater. The dispersion was spray coated onto a cotton knitted padto achieve an add-on within a range of area weights between 10 to 500g/m². An impregnated flat textile-like structure was obtained onevaporating the aqueous ethanol.

[0585] Indication:

[0586] Suitable for use in preparation of dressing materials for e.g.covering skin lesions after surgical removal of skin neoplasies.

[0587] The invention is not limited to the embodiments hereinbeforedescribed which may be varied in detail.

1. Biocompatible intermolecular polymer complex of: an anionic componentcomprising a linear or branched polysaccharide chain wherein at least 5%of the basic structural units are glucuronic acid; and a non proteincationic component comprising a linear or branched natural,semi-synthetic or synthetic oligomer or polymer.
 2. A complex as claimedin claim 1 wherein the cationic component contains nitrogen that eithercarries a positive charge or wherein the positive charge is induced bycontact with the polysaccharidic anionic component.
 3. A complex asclaimed in claim 2 wherein the cationic component is selected fromderivatives of acrylamide, methacrylamide and copolymers thereof,preferably the cationic component is selected from polyacrylamide,copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide,copolymers of acrylamide, butylacrylate, maleinanhydride and/ormethylmetacrylate.
 4. A complex as claimed in claim 1 wherein thecationic component is a cationised natural polysaccharide.
 5. A complexas claimed in claim 5 wherein the polysaccharide is a starch, celluloseor gum, preferably the gum is guargumhydroxypropyltriammonium chloride.6. A complex as claimed in claim 1 wherein the cationic component is asynthetic or semi-synthetic polyamino acid, preferably the cationiccomponent is polylysin, polyarginin, orα,β-poly-[N-(2-hydroxyethyl)-DL-aspartamide].
 7. A complex as claimed inclaim 1 wherein the cationic component is a synthetic anti-fibrinolytic,preferably the anti-fibrinolytic is a hexadimethrindibromide (polybren).8. A complex as claimed in claim 1 wherein the cationic component is anatural or semi-synthetic peptide, preferably the peptide is aprotamine, gelatine, fibrinopeptide, or derivatives thereof.
 9. Acomplex as claimed in claim 1 wherein the cationic component is anaminoglucane or derivatives thereof, preferably the aminoglucane isfractionated chitin or its de-acetylated derivative chitosan, preferablythe aminoglucane is of microbial origin or is isolated from the shellsof arthropods such as crabs.
 10. A complex as claimed in claim 1 whereinthe anionic component is polyanhydroglucuronic acid [PAGA].
 11. Acomplex as claimed in claim 10 wherein the polyanhydroglucuronic acidand salts thereof contain in their polymeric chain from 8 to 30 percentby weight of carboxyl groups, at least 80 percent by weight of thesegroups being of the uronic type, at most 5 percent by weight of carbonylgroups, and at most 0.5 percent by weight of bound nitrogen.
 12. Acomplex as claimed in claim 11 wherein the polyanhydroglucuronic acidand salts thereof contain in their polymeric chain at most 0.2 percentby weight of bound nitrogen.
 13. A complex as claimed in claim 11wherein the molecular mass of the polymeric chain of the anioniccomponent is from 1×10³ to 3×10⁵ Daltons, preferably the molecular massof the polymeric chain of the anionic component ranges from 5×10³ to1.5×10⁵ Daltons.
 14. A complex as claimed in claim 11 wherein thecontent of carboxyl groups is in the range of from 12 to 26 percent byweight, at least 95 percent of these groups being of the uronic type.15. A complex as claimed in claim 11 wherein the anionic componentcontains at most 1 percent by weight of carbonyl groups.
 16. A complexas claimed in claim 11 wherein the carbonyl groups are intra- andintermolecular 2,6 and 3,6 hemiacetals, 2,4 hemialdals and C2-C3aldehydes.
 17. A complex as claimed in claim 1 wherein the cationiccomponent is gelatine.
 18. A complex as claimed in claim 1 wherein thecationic component is chitosan.
 19. A pharmaceutical or cosmeticcomposition including at least one biocompatible complex as claimed inclaim
 1. 20. A composition as claimed in claim 19 including at least onebiocompatible biologically active substance.
 21. A composition asclaimed in claim 19 including at least one biologically acceptableadjuvant.
 22. A pharmaceutical composition for the prophylaxis ortreatment of peptic ulcers including a complex as claimed in claim 1.23. A slow release formulation including a complex as claimed inclaim
 1. 24. An antilipemic composition including a complex as claimedin claim
 1. 25. A suppository formulation including a complex as claimedin claim
 1. 26. A tablet including a complex as claimed in claim
 1. 27.A pellet including a complex as claimed in claim
 1. 28. A granuleincluding a complex as claimed in claim
 1. 29. A microsphere including acomplex as claimed in claim
 1. 30. A flat flexible material including acomplex as claimed in claim
 1. 31. A textile-like fabric including acomplex as claimed in claim
 1. 32. A foam including a complex as claimedin claim
 1. 33. A dental pin including a complex as claimed in claim 1.